Roflumilast

DALIRESP ® is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. DALIRESP is a selective phosphodiesterase 4 inhibitor indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. Limitations of Use: • DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm. • DALIRESP 250 mcg is a starting dose, for the first 4 weeks of treatment only and is not the effective (therapeutic) dose. Limitations of Use DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm. DALIRESP 250 mcg is a starting dose, for the first 4 weeks of treatment only and is not the effective (therapeutic) dose.

Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4). Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic-3′,5′-adenosine monophosphate (cyclic AMP)-metabolizing enzyme in lung tissue) activity leads to accumulation of intracellular cyclic AMP. While the specific mechanism(s) by which DALIRESP exerts its therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in lung cells.

The maintenance dose of DALIRESP is one 500 micrograms (mcg) tablet per day, with or without food. Starting treatment with a dose of DALIRESP 250 mcg once daily for 4 weeks and increasing to DALIRESP 500 mcg once daily thereafter may reduce the rate of treatment discontinuation in some patients. However, 250 mcg per day is not the effective (therapeutic) dose. The maintenance dose for patients with COPD is one 500 mcg tablet per day, with or without food.

The use of DALIRESP is contraindicated in the following condition: Moderate to severe liver impairment (Child-Pugh B or C). Moderate to severe liver impairment (Child-Pugh B or C)

• Acute Bronchospasm: Do not use for the relief of acute bronchospasm. • Psychiatric Events including Suicidality: Advise patients, their caregivers, and families to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Carefully weigh the risks and benefits of treatment with DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior. • Weight Decrease: Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of DALIRESP. • Drug Interactions: Use with strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) is not recommended.

The following adverse reactions are described in greater detail in other sections: • Psychiatric Events Including Suicidality • Weight Decrease Most common adverse reactions (≥2%) are diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness and decreased appetite.

A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. Use with inhibitors of CYP3A4 or dual inhibitors of CYP3A4 and CYP1A2 (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) will increase roflumilast systemic exposure and may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit.

Store DALIRESP tablets at 20° - 25°C (68° - 77°F), excursions permitted to 15° - 30°C (59° - 86°F).